دورية أكاديمية
Notch signaling without the APH-2/nicastrin subunit of gamma secretase in Caenorhabditis elegans germline stem cells.
| العنوان: | Notch signaling without the APH-2/nicastrin subunit of gamma secretase in Caenorhabditis elegans germline stem cells. |
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| المؤلفون: | Brinkley DM; Program in Biochemistry and Biophysics, Amherst College, Amherst, MA 01002, USA., Smith KC; Department of Biology, Amherst College, Amherst, MA 01002, USA., Fink EC; Department of Biology, Amherst College, Amherst, MA 01002, USA., Kwen W; Department of Biology, Amherst College, Amherst, MA 01002, USA., Yoo NH; Department of Biology, Amherst College, Amherst, MA 01002, USA., West Z; Department of Biology, Amherst College, Amherst, MA 01002, USA., Sullivan NL; Department of Biology, Amherst College, Amherst, MA 01002, USA., Farthing AS; Program in Biochemistry and Biophysics, Amherst College, Amherst, MA 01002, USA., Hale VA; Department of Biology, Amherst College, Amherst, MA 01002, USA., Goutte C; Program in Biochemistry and Biophysics, Amherst College, Amherst, MA 01002, USA.; Department of Biology, Amherst College, Amherst, MA 01002, USA. |
| المصدر: | Genetics [Genetics] 2024 Jul 08; Vol. 227 (3). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0374636 Publication Model: Print Cited Medium: Internet ISSN: 1943-2631 (Electronic) Linking ISSN: 00166731 NLM ISO Abbreviation: Genetics Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [Oxford] : Oxford University Press Original Publication: Austin, Tex. [etc.] |
| مواضيع طبية MeSH: | Caenorhabditis elegans*/metabolism , Caenorhabditis elegans*/genetics , Receptors, Notch*/metabolism , Receptors, Notch*/genetics , Caenorhabditis elegans Proteins*/metabolism , Caenorhabditis elegans Proteins*/genetics , Amyloid Precursor Protein Secretases*/metabolism , Amyloid Precursor Protein Secretases*/genetics , Signal Transduction* , Germ Cells*/metabolism, Animals ; Stem Cells/metabolism ; Stem Cells/cytology ; Membrane Glycoproteins/metabolism ; Membrane Glycoproteins/genetics |
| مستخلص: | The final step in Notch signaling activation is the transmembrane cleavage of Notch receptor by γ secretase. Thus far, genetic and biochemical evidence indicates that four subunits are essential for γ secretase activity in vivo: presenilin (the catalytic core), APH-1, PEN-2, and APH-2/nicastrin. Although some γ secretase activity has been detected in APH-2/nicastrin-deficient mammalian cell lines, the lack of biological relevance for this activity has left the quaternary γ secretase model unchallenged. Here, we provide the first example of in vivo Notch signal transduction without APH-2/nicastrin. The surprising dispensability of APH-2/nicastrin is observed in Caenorhabditis elegans germline stem cells (GSCs) and contrasts with its essential role in previously described C. elegans Notch signaling events. Depletion of GLP-1/Notch, presenilin, APH-1, or PEN-2 causes a striking loss of GSCs. In contrast, aph-2/nicastrin mutants maintain GSCs and exhibit robust and localized expression of the downstream Notch target sygl-1. Interestingly, APH-2/nicastrin is normally expressed in GSCs and becomes essential under conditions of compromised Notch function. Further insight is provided by reconstituting the C. elegans γ secretase complex in yeast, where we find that APH-2/nicastrin increases but is not essential for γ secretase activity. Together, our results are most consistent with a revised model of γ secretase in which the APH-2/nicastrin subunit has a modulatory, rather than obligatory role. We propose that a trimeric presenilin-APH-1-PEN-2 γ secretase complex can provide a low level of γ secretase activity, and that cellular context determines whether or not APH-2/nicastrin is essential for effective Notch signal transduction. Competing Interests: Conflicts of interest The authors declare no conflicts of interest. (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| معلومات مُعتمدة: | Amherst College Gregory S. Call Student Research Fund; H. Axel Schupf '57 Fund for Intellectual Life; 2117798 National Science Foundation; Caenorhabditis Genetics Center; P40 OD-010440 National Institutes of Health Office of Research Infrastructure Programs |
| فهرسة مساهمة: | Keywords: APH-1; HOP-1; Notch; SEL-12; gamma secretase; germline; presenilin; stem cells |
| المشرفين على المادة: | 0 (Receptors, Notch) 0 (Caenorhabditis elegans Proteins) EC 3.4.- (Amyloid Precursor Protein Secretases) 0 (nicastrin protein) 0 (Membrane Glycoproteins) |
| تواريخ الأحداث: | Date Created: 20240508 Date Completed: 20240708 Latest Revision: 20240801 |
| رمز التحديث: | 20240801 |
| DOI: | 10.1093/genetics/iyae076 |
| PMID: | 38717968 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1943-2631 |
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| DOI: | 10.1093/genetics/iyae076 |